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1.
Nat Cell Biol ; 21(2): 190-202, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30598531

RESUMO

Cytotoxic chemotherapy is an effective treatment for invasive breast cancer. However, experimental studies in mice also suggest that chemotherapy has pro-metastatic effects. Primary tumours release extracellular vesicles (EVs), including exosomes, that can facilitate the seeding and growth of metastatic cancer cells in distant organs, but the effects of chemotherapy on tumour-derived EVs remain unclear. Here we show that two classes of cytotoxic drugs broadly employed in pre-operative (neoadjuvant) breast cancer therapy, taxanes and anthracyclines, elicit tumour-derived EVs with enhanced pro-metastatic capacity. Chemotherapy-elicited EVs are enriched in annexin A6 (ANXA6), a Ca2+-dependent protein that promotes NF-κB-dependent endothelial cell activation, Ccl2 induction and Ly6C+CCR2+ monocyte expansion in the pulmonary pre-metastatic niche to facilitate the establishment of lung metastasis. Genetic inactivation of Anxa6 in cancer cells or Ccr2 in host cells blunts the pro-metastatic effects of chemotherapy-elicited EVs. ANXA6 is detected, and potentially enriched, in the circulating EVs of breast cancer patients undergoing neoadjuvant chemotherapy.


Assuntos
Doxorrubicina/uso terapêutico , Vesículas Extracelulares/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Paclitaxel/uso terapêutico , Animais , Anexina A6/metabolismo , Linhagem Celular Tumoral , Quimiocina CCL2/metabolismo , Vesículas Extracelulares/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Camundongos Transgênicos
2.
J Immunol ; 202(4): 1069-1078, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30659109

RESUMO

Genetic variants in C5orf30 have been associated with development of the autoimmune conditions primary biliary cirrhosis and rheumatoid arthritis. In rheumatoid arthritis, C5orf30 expression is cell-specific, with highest expression found in macrophages and synovial fibroblasts. C5orf30 is highly expressed in inflamed joints and is a negative regulator of tissue damage in a mouse model of inflammatory arthritis. Transcriptomic analysis from ultrasound-guided synovial biopsy of inflamed joints in a well characterized clinical cohort of newly diagnosed, disease-modifying antirheumatic drugs-naive rheumatoid arthritis patients was used to determine the clinical association of C5orf30 expression with disease activity. A combined molecular and computational biology approach was used to elucidate C5orf30 function in macrophages both in vitro and in vivo. Synovial expression of C5orf30 is inversely correlated with both clinical measures of rheumatoid arthritis disease activity and with synovial TNF mRNA expression. C5orf30 plays a role in regulating macrophage phenotype and is differentially turned over in inflammatory and anti-inflammatory macrophages. Inhibition of C5orf30 reduces wound healing/repair-associated functions of macrophages, reduces signaling required for resolution of inflammation, and decreases secretion of anti-inflammatory mediators. In an animal model of wound healing (zebrafish), C5orf30 inhibition increases the recruitment of macrophages to the wound site. Finally, we demonstrate that C5orf30 skews macrophage immunometabolism, demonstrating a mechanism for C5orf30-mediated immune regulation.


Assuntos
Artrite Reumatoide/imunologia , Proteínas de Transporte/genética , Inflamação/imunologia , Macrófagos/imunologia , Animais , Antirreumáticos/farmacologia , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Proteínas de Transporte/antagonistas & inibidores , Células Cultivadas , Estudos de Coortes , Humanos , Inflamação/diagnóstico , Inflamação/tratamento farmacológico , Inflamação/genética , Macrófagos/efeitos dos fármacos , Fosfoproteínas , Cicatrização/efeitos dos fármacos , Cicatrização/imunologia , Peixe-Zebra
3.
J Bone Miner Res ; 34(5): 783-796, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30320927

RESUMO

Multiple myeloma is a plasma cell malignancy, which develops in the bone marrow and frequently leads to severe bone destruction. Current antiresorptive therapies to treat the bone disease do little to repair damaged bone; therefore, new treatment strategies incorporating bone anabolic therapies are urgently required. We hypothesized that combination therapy using the standard of care antiresorptive zoledronic acid (Zol) with a bone anabolic (anti-TGFß/1D11) would be more effective at treating myeloma-induced bone disease than Zol therapy alone. JJN3 myeloma-bearing mice (n = 8/group) treated with combined Zol and 1D11 resulted in a 48% increase (p ≤ 0.001) in trabecular bone volume (BV/TV) compared with Zol alone and a 65% increase (p ≤ 0.0001) compared with 1D11 alone. Our most significant finding was the substantial repair of U266-induced osteolytic bone lesions with combination therapy (n = 8/group), which resulted in a significant reduction in lesion area compared with vehicle (p ≤ 0.01) or Zol alone (p ≤ 0.01). These results demonstrate that combined antiresorptive and bone anabolic therapy is significantly more effective at preventing myeloma-induced bone disease than Zol alone. Furthermore, we demonstrate that combined therapy is able to repair established myelomatous bone lesions. This is a highly translational strategy that could significantly improve bone outcomes and quality of life for patients with myeloma. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

4.
Expert Opin Drug Discov ; 12(4): 379-389, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28277839

RESUMO

INTRODUCTION: Patients with metastatic cancer suffer the highest rate of cancer-related death, but existing animal models of metastasis have disadvantages that limit our ability to understand this process. The zebrafish is increasingly used for cancer modelling, particularly xenografting of human cancer cell lines, and drug discovery, and may provide novel scientific and therapeutic insights. However, this model system remains underexploited. Areas covered: The authors discuss the advantages and disadvantages of the zebrafish xenograft model for the study of cancer, metastasis and drug discovery. They summarise previous work investigating the metastatic cascade, such as tumour-induced angiogenesis, intravasation, extravasation, dissemination and homing, invasion at secondary sites, assessing metastatic potential and evaluation of cancer stem cells in zebrafish. Expert opinion: The practical advantages of zebrafish for basic biological study and drug discovery are indisputable. However, their ability to sufficiently reproduce and predict the behaviour of human cancer and metastasis remains unproven. For this to be resolved, novel mechanisms must to be discovered in zebrafish that are subsequently validated in humans, and for therapeutic interventions that modulate cancer favourably in zebrafish to successfully translate to human clinical studies. In the meantime, more work is required to establish the most informative methods in zebrafish.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas/métodos , Neoplasias/tratamento farmacológico , Animais , Humanos , Metástase Neoplásica , Neoplasias/patologia , Células-Tronco Neoplásicas/metabolismo , Neovascularização Patológica/patologia , Especificidade da Espécie , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Peixe-Zebra
5.
Sci Rep ; 6: 36023, 2016 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-27777406

RESUMO

Porphyromonas gingivalis (Pg) is a keystone pathogen in the aetiology of chronic periodontitis. However, recent evidence suggests that the bacterium is also able to enter the bloodstream, interact with host cells and tissues, and ultimately contribute to the pathogenesis of cardiovascular disease (CVD). Here we established a novel zebrafish larvae systemic infection model showing that Pg rapidly adheres to and penetrates the zebrafish vascular endothelium causing a dose- and time-dependent mortality with associated development of pericardial oedemas and cardiac damage. The in vivo model was then used to probe the role of Pg expressed gingipain proteases using systemically delivered gingipain-deficient Pg mutants, which displayed significantly reduced zebrafish morbidity and mortality compared to wild-type bacteria. In addition, we used the zebrafish model to show efficacy of a gingipain inhibitor (KYT) on Pg-mediated systemic disease, suggesting its potential use therapeutically. Our data reveal the first real-time in vivo evidence of intracellular Pg within the endothelium of an infection model and establishes that gingipains are crucially linked to systemic disease and potentially contribute to CVD.


Assuntos
Adesinas Bacterianas/metabolismo , Doenças Cardiovasculares/microbiologia , Cisteína Endopeptidases/metabolismo , Endotélio Vascular/microbiologia , Periodontite/microbiologia , Porphyromonas gingivalis/patogenicidade , Adesinas Bacterianas/genética , Animais , Doenças Cardiovasculares/patologia , Cisteína Endopeptidases/genética , Larva/microbiologia , Porphyromonas gingivalis/genética , Peixe-Zebra/embriologia
6.
Cancer Res ; 75(17): 3479-91, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26269531

RESUMO

Tumor relapse after chemotherapy-induced regression is a major clinical problem, because it often involves inoperable metastatic disease. Tumor-associated macrophages (TAM) are known to limit the cytotoxic effects of chemotherapy in preclinical models of cancer. Here, we report that an alternatively activated (M2) subpopulation of TAMs (MRC1(+)TIE2(Hi)CXCR4(Hi)) accumulate around blood vessels in tumors after chemotherapy, where they promote tumor revascularization and relapse, in part, via VEGF-A release. A similar perivascular, M2-related TAM subset was present in human breast carcinomas and bone metastases after chemotherapy. Although a small proportion of M2 TAMs were also present in hypoxic tumor areas, when we genetically ablated their ability to respond to hypoxia via hypoxia-inducible factors 1 and 2, tumor relapse was unaffected. TAMs were the predominant cells expressing immunoreactive CXCR4 in chemotherapy-treated mouse tumors, with the highest levels expressed by MRC1(+) TAMs clustering around the tumor vasculature. Furthermore, the primary CXCR4 ligand, CXCL12, was upregulated in these perivascular sites after chemotherapy, where it was selectively chemotactic for MRC1(+) TAMs. Interestingly, HMOX-1, a marker of oxidative stress, was also upregulated in perivascular areas after chemotherapy. This enzyme generates carbon monoxide from the breakdown of heme, a gas known to upregulate CXCL12. Finally, pharmacologic blockade of CXCR4 selectively reduced M2-related TAMs after chemotherapy, especially those in direct contact with blood vessels, thereby reducing tumor revascularization and regrowth. Our studies rationalize a strategy to leverage chemotherapeutic efficacy by selectively targeting this perivascular, relapse-promoting M2-related TAM cell population.


Assuntos
Neoplasias da Mama/genética , Macrófagos/patologia , Recidiva Local de Neoplasia/genética , Neovascularização Patológica/genética , Receptores CXCR4/biossíntese , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/patologia , Quimiocina CXCL12/biossíntese , Quimiocina CXCL12/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Macrófagos/metabolismo , Camundongos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neovascularização Patológica/tratamento farmacológico , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/genética , Transdução de Sinais/efeitos dos fármacos , Tamoxifeno/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/genética
7.
BMJ Open Gastroenterol ; 2(1): e000052, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26719813

RESUMO

BACKGROUND: Vitamin D deficiency has been associated or implicated with the pathophysiology of the gastrointestinal conditions inflammatory bowel disease and colorectal cancer, as well as with depression. No trials or epidemiology studies to date have investigated a link with irritable bowel syndrome (IBS). A single case report has suggested a benefit in IBS of vitamin D supplementation. We hypothesised that IBS participants with vitamin D insufficiency would benefit from repletion in terms of their IBS symptoms. We undertook a pilot trial to provide data to support a power calculation and to justify a full trial. METHODS: This was a randomised, double blinded, three-arm parallel design trial of vitamin D, placebo or a combination of vitamin D and probiotics. Participants were further stratified according to whether they were vitamin D replete or insufficient. Vitamin D status was determined by blood test at baseline and exit; IBS symptoms were assessed by validated questionnaire; dietary intakes were assessed by food frequency questionnaire. RESULTS: A significant proportion of the IBS population were vitamin D deficient, such that the replete stratum could not be adequately recruited. There was a significant association in the baseline data between circulating vitamin D level and quality of life ("How much has IBS affected your life?"). Supplementation significantly improved vitamin D level versus placebo. IBS symptoms were not significantly improved in this pilot, although a power calculation was enabled from the intervention data. CONCLUSIONS: The IBS population exhibits significant levels of vitamin D insufficiency and would benefit from screening and possible supplementation. The impact of IBS on quality of life may be reduced by vitamin D level. Future trials should have a sample size of over 97. TRIAL REGISTRATION NUMBER: ICTRN 6116003917.

8.
Hypoxia (Auckl) ; 2: 185-196, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-27774476

RESUMO

Hypoxia plays a critical role in the pathobiology of various inflamed, diseased tissues, including malignant tumors, atherosclerotic plaques, myocardial infarcts, the synovia of rheumatoid arthritic joints, healing wounds, and sites of bacterial infection. These areas of hypoxia form when the blood supply is occluded and/or the oxygen supply is unable to keep pace with cell growth and/or infiltration of inflammatory cells. Macrophages are ubiquitous in all tissues of the body and exhibit great plasticity, allowing them to perform divergent functions, including, among others, patrolling tissue, combating invading pathogens and tumor cells, orchestrating wound healing, and restoring homeostasis after an inflammatory response. The number of tissue macrophages increases markedly with the onset and progression of many pathological states, with many macrophages accumulating in avascular and necrotic areas, where they are exposed to hypoxia. Recent studies show that these highly versatile cells then respond rapidly to the hypoxia present by altering their expression of a wide array of genes. Here we review the evidence for hypoxia-driven macrophage inflammatory responses in various disease states, and how this influences disease progression and treatment.

9.
Dis Model Mech ; 7(2): 259-64, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24203886

RESUMO

Interleukin-1 (IL-1), the 'gatekeeper' of inflammation, is the apical cytokine in a signalling cascade that drives the early response to injury or infection. Expression, processing and secretion of IL-1 are tightly controlled, and dysregulated IL-1 signalling has been implicated in a number of pathologies ranging from atherosclerosis to complications of infection. Our understanding of these processes comes from in vitro monocytic cell culture models as lines or primary isolates, in which a range and spectra of IL-1 secretion mechanisms have been described. We therefore investigated whether zebrafish embryos provide a suitable in vivo model for studying IL-1-mediated inflammation. Structurally, zebrafish IL-1ß shares a ß-sheet-rich trefoil structure with its human counterpart. Functionally, leukocyte expression of IL-1ß was detectable only following injury, which activated leukocytes throughout zebrafish embryos. Migration of macrophages and neutrophils was attenuated by inhibitors of either caspase-1 or P2X7, which similarly inhibited the activation of NF-κB at the site of injury. Zebrafish offer a new and versatile model to study the IL-1ß pathway in inflammatory disease and should offer unique insights into IL-1 biology in vivo.


Assuntos
Caspase 1/metabolismo , Inflamação/patologia , Interleucina-1beta/metabolismo , Regulação para Cima , Peixe-Zebra/metabolismo , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Nadadeiras de Animais/efeitos dos fármacos , Nadadeiras de Animais/patologia , Animais , Inibidores de Caspase/farmacologia , Sequência Conservada , Regulação para Baixo/efeitos dos fármacos , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Embrião não Mamífero/patologia , Humanos , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , NF-kappa B/metabolismo , Corantes de Rosanilina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Peixe-Zebra/embriologia
10.
Arterioscler Thromb Vasc Biol ; 33(6): 1257-63, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23559631

RESUMO

OBJECTIVE: Coarctation of the aorta is rarely associated with known gene defects. Blomstrand chondrodysplasia, caused by mutations in the parathyroid hormone receptor 1 (PTHR1) is associated with coarctation of the aorta in some cases, although it is unclear whether PTHR1 deficiency causes coarctation of the aorta directly. The zebrafish allows the study of vascular development using approaches not possible in other models. We therefore examined the effect of loss of function of PTHR1 or its ligand parathyroid hormone-related peptide (PTHrP) on aortic formation in zebrafish. APPROACH AND RESULTS: Morpholino antisense oligonucleotide knockdown of either PTHR1 or PTHrP led to a localized occlusion of the mid-aorta in developing zebrafish. Confocal imaging of transgenic embryos showed that these defects were caused by loss of endothelium, rather than failure to lumenize. Using a Notch reporter transgenic ([CSL:Venus]qmc61), we found both PTHR1 and PTHrP knockdown-induced defective Notch signaling in the hypochord at the site of the aortic defect before onset of circulation, and the aortic occlusion was rescued by inducible Notch upregulation. CONCLUSIONS: Loss of function of either PTHR1 or PTHrP leads to a localized aortic defect that is Notch dependent. These findings may underlie the aortic defect seen in Blomstrand chondrodysplasia, and reveal a link between parathyroid hormone and Notch signaling during aortic development.


Assuntos
Aorta/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Proteínas do Tecido Nervoso/genética , Receptor Notch1/genética , Receptor Tipo 1 de Hormônio Paratireóideo/genética , Transdução de Sinais/genética , Proteínas de Peixe-Zebra/genética , Animais , Coartação Aórtica/genética , Coartação Aórtica/fisiopatologia , Feminino , Masculino , Modelos Animais , Mutação/genética , Neovascularização Fisiológica/genética , Valores de Referência , Regulação para Cima , Peixe-Zebra
11.
Semin Cancer Biol ; 23(3): 149-58, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23410638

RESUMO

Neutrophils are rapidly responding, phagocytes that are an essential part of the host innate immune response to invading micro-organisms. Along with other leucocytes they also play a key role in directing repair at sites of tissue damage. Neutrophils accomplish many of their biological functions by releasing enzymes, anti-microbial agents and cytokines when stimulated to degranulate. There is now increasing evidence to show that tumours are able to recruit neutrophils by secreting a number of tumour cell or stromal-derived chemoattractants. Once within the tumour microenvironment neutrophils, like macrophages, are polarised into a pro-tumour phenotype that can foster tumour growth by secreting factors that directly influence tumour cell proliferation, drive immunosuppression and promote tumour angiogenesis. In this review we discuss the likely mechanisms by which neutrophils are recruited into the tumour and then elaborate on how these cells may induce tumour vascularisation by the secretion of powerful pro-angiogenic factors.


Assuntos
Neoplasias/irrigação sanguínea , Neoplasias/imunologia , Neovascularização Patológica/imunologia , Neutrófilos/imunologia , Animais , Fatores Quimiotáticos/imunologia , Fatores Quimiotáticos/metabolismo , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Neovascularização Patológica/metabolismo , Infiltração de Neutrófilos/imunologia , Neutrófilos/metabolismo , Carga Tumoral/imunologia
12.
Cancer Res ; 73(2): 490-5, 2013 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-23172310

RESUMO

Frontline anticancer therapies such as chemotherapy and irradiation often slow tumor growth, but tumor regrowth and spread to distant sites usually occurs after the conclusion of treatment. We recently showed that macrophages could be used to deliver large quantities of a hypoxia-regulated, prostate-specific oncolytic virus (OV) to prostate tumors. In the current study, we show that administration of such OV-armed macrophages 48 hours after chemotherapy (docetaxel) or tumor irradiation abolished the posttreatment regrowth of primary prostate tumors in mice and their spread to the lungs for up to 27 or 40 days, respectively. It also significantly increased the lifespan of tumor-bearing mice compared with those given docetaxel or irradiation alone. These new findings suggest that such a novel, macrophage-based virotherapy could be used to markedly increase the efficacy of chemotherapy and irradiation in patients with prostate cancer.


Assuntos
Macrófagos/virologia , Terapia Viral Oncolítica/métodos , Neoplasias da Próstata/terapia , Taxoides/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Terapia Combinada , Docetaxel , Humanos , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Masculino , Camundongos , Neoplasias da Próstata/radioterapia , Recidiva , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Int J Cancer ; 129(4): 847-58, 2011 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-21328342

RESUMO

Neutrophils are important innate immune cells that are involved in microbial clearance at sites of infection and in wound healing. The microenvironment of tumors often resembles that of chronic inflammation and increased numbers of neutrophils have been observed in several tumors and, in some cases, these positively correlate with poor prognosis. Neutrophil recruitment into tumors appears to be dependent on chemokines that bind to CXCR1 and CXCR2 expressed by neutrophils. In our study, we used lung adenocarcinoma A549 multicellular tumor spheroids and A549 tumor xenografts along with a CXCR2-specific small molecule inhibitor (AZ10397767) to investigate the recruitment and function of human neutrophils in tumors. We found that A549 spheroids constitutively secrete high levels of CXCL chemokines and that neutrophil recruitment into A549 tumors in vitro and in vivo is largely dependent on CXCR2 activation. AZ10397767 significantly reduced the numbers of infiltrating neutrophils into both in vitro and in vivo tumor models, which was associated with slower growing tumors. Neutrophil infiltration into A549 tumor spheroids increased their size compared to noninfiltrated spheroids and neutrophil-derived factors increased the proliferation of A549 tumor cells and induced endothelial cell tubule formation in vitro. In contrast, we saw no reduction in microvascular density in AZ10397767-treated A549 tumors or in tumors grown in CXCR2(-/-) mice, suggesting that angiogenesis in these tumors is CXCR2-independent. Our data show that neutrophils can contribute to lung tumor growth and that CXCR2 antagonists may be a useful therapeutic agent in the treatment of lung carcinomas.


Assuntos
Adenocarcinoma/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/tratamento farmacológico , Infiltração de Neutrófilos/efeitos dos fármacos , Quinazolinas/uso terapêutico , Receptores de Interleucina-8B/antagonistas & inibidores , Triazóis/uso terapêutico , Adenocarcinoma/imunologia , Adenocarcinoma/metabolismo , Animais , Western Blotting , Proliferação de Células , Quimiotaxia , Meios de Cultivo Condicionados/farmacologia , Ensaio de Imunoadsorção Enzimática , Humanos , Técnicas Imunoenzimáticas , Técnicas In Vitro , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Melanoma/imunologia , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , RNA Mensageiro/genética , Receptores de Interleucina-8B/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esferoides Celulares , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Int J Exp Pathol ; 90(3): 222-31, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19563607

RESUMO

It is now well known that most malignant tumours contain a significant amount of leucocytic infiltrates the presence of which has, on many occasions, been linked to poor patient prognosis. These leucocyte populations are recruited to tumours by chemotactic factors released by either viable or necrotic tumour cells, or by cells within the tumour stroma. In recent times, most studies have analysed the role that tumour-associated macrophages (TAM) have on tumour progression. However, there is now increasing evidence to show that neutrophils also actively participate in this process. Whilst there are some data to suggest that neutrophil-derived factors can promote genetic mutations leading to tumourigenesis, or secrete factors that promote tumour cell proliferation; there is now substantial evidence to show that neutrophils, like TAM, significantly affect tumour angiogenesis. In this review, we discuss the likely mechanisms by which neutrophils are recruited into the tumour and then elaborate on how these cells may induce tumour vascularization by the secretion of powerful pro-angiogenic factors. We also discuss possible future chemotherapeutic strategies that are aimed at limiting tumour angiogenesis by inhibiting neutrophil recruitment.


Assuntos
Neoplasias/irrigação sanguínea , Neovascularização Patológica/patologia , Neutrófilos/fisiologia , Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Humanos , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos
15.
Neoplasia ; 10(4): 329-40, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18392134

RESUMO

Previous studies in the K14-HPV/E(2) mouse model of cervical carcinogenesis demonstrated that infiltrating macrophages are the major source of matrix metalloproteinase 9 (MMP-9), a metalloprotease important for tumor angiogenesis and progression. We observed increased expression of the macrophage chemoattractant, CCL2, and its receptor, CCR2, concomitant with macrophage influx and MMP-9 expression. To study the role of CCL2-CCR2 signaling in cervical tumorigenesis, we generated CCR2-deficient K14-HPV/E(2) mice. Cervixes of CCR2-null mice contained significantly fewer macrophages. Surprisingly, there was only a modest delay in time to progression from dysplasia to carcinoma in the CCR2-deficient mice, and no difference in end-stage tumor incidence or burden. Moreover, there was an unexpected persistence of MMP-9 activity, associated with increased abundance of MMP-9(+) neutrophils in tumors from CCR2-null mice. In vitro bioassays revealed that macrophages produce soluble factor(s) that can suppress neutrophil dynamics, as evidenced by reduced chemotaxis in response to CXCL8, and impaired invasion into three-dimensional tumor masses grown in vitro. Our data suggest a mechanism whereby CCL2 attracts proangiogenic CCR2(+) macrophages with the ancillary capability to limit infiltration by neutrophils. If such tumor-promoting macrophages are suppressed, MMP-9(+) neutrophils are then recruited, providing alternative paracrine support for tumor angiogenesis and progression.


Assuntos
Carcinoma in Situ/imunologia , Neoplasia Intraepitelial Cervical/imunologia , Macrófagos/fisiologia , Neutrófilos/fisiologia , Neoplasias do Colo do Útero/imunologia , Animais , Carcinoma in Situ/metabolismo , Movimento Celular , Neoplasia Intraepitelial Cervical/metabolismo , Quimiocina CCL2/fisiologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Incidência , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Monócitos/patologia , Neovascularização Patológica , Lesões Pré-Cancerosas/imunologia , Lesões Pré-Cancerosas/metabolismo , Receptores CCR2/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esferoides Celulares/patologia , Neoplasias do Colo do Útero/metabolismo
16.
Cancer Lett ; 265(2): 239-49, 2008 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-18353538

RESUMO

The cytokine MIF is over-expressed in tumors and is associated with tumor proliferation, angiogenesis and metastasis. Hypoxia, a hallmark feature of tumors, increases MIF expression from tumor cells. We examined the role of hypoxia-inducible transcription factors on MIF secretion from MCF-7 breast carcinoma cells. Secretion of MIF was induced by hypoxia after 24h but up-regulation of MIF mRNA was minimal. Inhibition of HIF-1alpha, HIF-2alpha, NF-kappaB and C/EBPbeta using siRNA had no effect on hypoxia-induced MIF secretion. However, inhibition of transcription and translation significantly decreased MIF production, suggesting that hypoxia-induced secretion of MIF in MCF-7 cells is via an alternative pathway.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Neoplasias da Mama/metabolismo , Hipóxia Celular , Fatores Inibidores da Migração de Macrófagos/metabolismo , Técnicas de Cultura de Células/métodos , Linhagem Celular Tumoral , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , RNA Interferente Pequeno/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
17.
J Immunol ; 178(11): 7405-11, 2007 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-17513791

RESUMO

Angiopoietins 1 and 2 bind to Tie-2 expressed on endothelial cells and regulate vessel stabilization and angiogenesis. Tie-2(+) monocytes have been shown to be recruited to experimental tumors where they promote tumor angiogenesis. In this study, we show that 20% of CD14(+) human blood monocytes express Tie-2, and that these cells coexpress CD16 (FcgammaRIII) and are predominantly CD34 negative. Ang-2 is up-regulated by endothelial cells in malignant tumors and inflamed tissues, so our finding that Ang-2 is a chemoattractant for human Tie-2(+) monocytes and macrophages, suggests that it may help to recruit and regulate their distribution in such tissues. Ang-2 was also found to markedly inhibit release of the important proinflammatory cytokine, TNF-alpha, by monocytes in vitro. Following extravasation of monocytes, and their differentiation into macrophages, many accumulate in the hypoxic areas of inflamed and malignant tissues. Ang-2 is known to be up-regulated by hypoxia and we show that monocytes and macrophages up-regulate Tie-2 when exposed to hypoxia. Furthermore, hypoxia augmented the inhibitory effect of Ang-2 on the release of the anti-angiogenic cytokine, IL-12 by monocytes. In sum, our data indicate that Ang-2 may recruit Tie-2(+) monocytes to tumors and sites of inflammation, modulate their release of important cytokines and stimulate them to express a proangiogenic phenotype.


Assuntos
Angiopoietina-2/fisiologia , Regulação da Expressão Gênica/imunologia , Monócitos/enzimologia , Receptor TIE-2/biossíntese , Receptor TIE-2/genética , Animais , Hipóxia Celular/imunologia , Membrana Celular/enzimologia , Membrana Celular/imunologia , Membrana Celular/patologia , Células Cultivadas , Quimiotaxia de Leucócito/imunologia , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Granulócitos/enzimologia , Granulócitos/metabolismo , Granulócitos/patologia , Humanos , Mediadores da Inflamação/fisiologia , Subpopulações de Linfócitos/enzimologia , Subpopulações de Linfócitos/metabolismo , Subpopulações de Linfócitos/patologia , Macrófagos/enzimologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Monócitos/metabolismo , Monócitos/patologia , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/enzimologia , Neoplasias Experimentais/patologia , Neovascularização Patológica/imunologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptor TIE-2/fisiologia , Regulação para Cima/imunologia
18.
Int J Exp Pathol ; 85(5): 233-48, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15379956

RESUMO

Angiogenesis, the development of new blood vessels from an existing vasculature, is essential in normal developmental processes and in numerous pathologies, including diabetic retinopathy, psoriasis and tumour growth and metastases. One of the problems faced by angiogenesis researchers has been the difficulty of finding suitable methods for assessing the effects of regulators of the angiogenic response. The ideal assay would be reliable, technically straightforward, easily quantifiable and, most importantly, physiologically relevant. Here, we review the advantages and limitations of the principal assays in use, including those for the proliferation, migration and differentiation of endothelial cells in vitro, vessel outgrowth from organ cultures and in vivo assays such as sponge implantation, corneal, chamber, zebrafish, chick chorioallantoic membrane (CAM) and tumour angiogenesis models.


Assuntos
Neovascularização Fisiológica/fisiologia , Moduladores da Angiogênese/análise , Animais , Bioensaio/métodos , Diferenciação Celular/fisiologia , Divisão Celular/fisiologia , Movimento Celular/fisiologia , Células Endoteliais/fisiologia , Endotélio Vascular/fisiologia , Membranas Extraembrionárias/fisiologia , Humanos , Neovascularização Patológica/fisiopatologia , Técnicas de Cultura de Órgãos/métodos
19.
Blood ; 103(2): 601-6, 2004 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-14512300

RESUMO

Angiogenesis, the development of new blood vessels from existing vasculature, is crucial for the development and metastasis of solid tumors. Here, we show for the first time that a 24-amino acid peptide derived from the amino terminus of the alpha chain of human fibrinogen (termed "alphastatin") has potent antiangiogenic properties, inhibiting both the migration and tubule formation of human dermal microvascular endothelial cells in response to vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) in vitro. Moreover, alphastatin markedly inhibits the growth of tumors in a syngeneic murine model. Tumors from mice receiving daily injections of alphastatin for 12 days exhibited large areas of intravascular disruption and thrombosis with substantial cellular necrosis. Importantly, alphastatin administration had no detectable effect on vessels in such normal tissues as liver, lungs, and kidney. Taken together, these data indicate that alphastatin is a potent new antiangiogenic agent in vitro and antivascular agent in vivo.


Assuntos
Inibidores da Angiogênese/farmacologia , Endotélio Vascular/fisiologia , Fibrinogênio/química , Fibrinogênio/farmacologia , Microcirculação/fisiologia , Neovascularização Patológica/prevenção & controle , Neovascularização Fisiológica/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Pele/irrigação sanguínea , Animais , Divisão Celular/efeitos dos fármacos , Quimiotaxia/efeitos dos fármacos , Quimiotaxia/fisiologia , Endotélio Vascular/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/irrigação sanguínea , Proteínas Recombinantes/farmacologia , Fator A de Crescimento do Endotélio Vascular/farmacologia
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